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The tumour microenvironment in B cell lymphomas

Nature Reviews Cancer volume 14, pages 517–534 (2014)Cite this article

Subjects

Key Points

  • B cell lymphomas show a range of extent and composition of tumour microenvironment components, partly reflecting tumour cell content and acquired genetic aberrations harboured by the lymphoma cells.

  • B cell lymphomas home to and co-opt the tumour microenvironment to derive survival and growth signals and to achieve escape from immune surveillance.

  • Tumour–microenvironment interactions are important contributors to both pathogenesis and prognosis of B cell lymphomas.

  • Some aspects of treatment resistance are mediated through tumour–microenvironment interactions, via factors secreted by stromal cells in response to lymphoma cells and cell adhesion-mediated drug resistance.

  • A fundamental understanding of tumour–microenvironment interactions underlies treatment strategies, including immune checkpoint blockade and separating lymphoma cells from their supportive microenvironment.

  • Future studies will include overlaying the genomic aberrations in the lymphoma cells on the composition of the tumour microenvironment and will aim to determine the functional consequences of these interactions.

Abstract

B cell lymphomas are cancers that arise from cells that depend on numerous highly orchestrated interactions with immune and stromal cells in the course of normal development. Despite the recent focus on dissecting the genetic aberrations within cancer cells, it has been increasingly recognized that tumour cells retain a range of dependence on interactions with the non-malignant cells and stromal elements that constitute the tumour microenvironment. A fundamental understanding of these interactions gives insight into the pathogenesis of most B cell lymphomas and, moreover, identifies novel therapeutic opportunities for targeting oncogenic pathways, both now and in the future.

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Figure 1: Composition of the B cell lymphoma microenvironment.
Figure 2: Survival and proliferation signals from the tumour microenvironment.
Figure 3: Interactions with the microenvironment that mediate immune escape.

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Acknowledgements

The authors receive research support from the Terry Fox Research Institute, Vancouver, Canada, the Canadian Institutes of Health Research, Genome Canada and Genome British Columbia and the Lymphoma Research Foundation US. The authors apologize to the numerous colleagues whose important contributions could not be included in this Review owing to space limitations.

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Authors and Affiliations

  1. Centre for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, V5Z 1L3, Canada

    David W. Scott & Randy D. Gascoyne

  2. Department of Pathology & Laboratory Medicine, University of British Columbia, Vancouver, V6T 2B5, Canada

    Randy D. Gascoyne

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  1. David W. Scott
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PowerPoint slides

Glossary

Lymphoid structures

These include the primary lymphoid organs (bone marrow and thymus), secondary or peripheral lymphoid organs (lymph nodes, spleen and mucosa-associated lymphoid tissue) and the tertiary lymphoid organs, which develop at sites of infection and chronic stimulation of the immune system.

Sclerosis

A hardening or thickening of the tissue owing to excessive growth of fibrous connective tissue.

Reactive germinal centres

Physiological germinal centres that are produced in response to an antigenic stimulus.

Follicular dendritic cells

(FDCs). Stromal cells of mesenchymal origin that are located in the B cell follicles of secondary lymphoid organs, where they present intact antigen to B cells undergoing the germinal centre reaction, thereby contributing to affinity maturation.

Follicular T helper cells

(TFH cells). A distinct set of antigen-experienced CD4+ T helper cells that are focused in the germinal centre and contribute to the affinity maturation of B cells.

Hodgkin Reed–Sternberg cells

(HRS cells). The pathognomonic neoplastic B cells of classical Hodgkin's lymphoma with characteristic morphology, immunophenotype and genetic alterations, including classic binucleate cells (Reed–Sternberg cells) and mononuclear variants (Hodgkin cells).

Tingible-body macrophages

A type of macrophage that is found physiologically in germinal centres, with their appearance related to the staining characteristics of phagocytosed debris from apoptotic cells.

Follicular regulatory T cells

(TFR cells). A set of regulatory T cells that are CXC-chemokine receptor 5 (CXCR5)+ and BCL-6+, localized to germinal centres and prevent excessive germinal centre reactions.

Co-stimulation

Appropriate activation of T cells involves binding of the antigen by the T cell receptor, together with other 'co-stimulatory' signals from the cell presenting the antigen.

Tumour-associated macrophage

A cell derived from circulating monocytes or tissue-resident macrophages that is found in close proximity to tumours or within them.

Paratrabecular

Pertaining to being located adjacent to the trabeculae of bone in the bone marrow.

Fibroblastic reticular cells

(FRCs). Stromal cells that make up the scaffold of the T cell zone of secondary lymphoid organs; they direct lymphocyte trafficking within the organs and they present antigens.

Autochthonous animal models

Models in which the tumours arise in organs that are typically infiltrated by the cancer, potentially allowing the impact of interactions between the microenvironment of these organs and the tumour cells to be examined.

Anti-idiotype treatment

This treatment uses monoclonal antibodies that specifically recognize unique determinants in the variable regions of immunoglobulins on the tumour cells.

Somatic hypermutation

(SHM). This process is mediated by the enzyme activation-induced (cytidine) deaminase (AID), occurring in B cells in the germinal centres, whereby the variable regions of the immunoglobulin genes are mutated, allowing for an increased specificity of antibody for antigen.

Antigen-presenting cells

These cells, which include dendritic cells, macrophages and some B cells, mediate cellular immune responses by presenting antigen in the context of major histocompatibility complex class II to T cells.

Cytotoxic T lymphocytes

(CTLs). CD8+ T cells that kill cells on the basis of the presentation by that cell of specific antigen recognized by the T cell receptor of the cytotoxic T cell.

Natural killer cells

(NK cells). A type of cytotoxic lymphocyte (part of the innate immune system) that has a role in killing tumour cells and virally infected cells without the requirement for antigen presentation in the context of major histocompatibility complex class I.

Immune checkpoint blockade

A strategy that involves blockade of the inhibitory ligands and/or receptors that modify the response of T cells to antigen presented to the T cell receptor, thereby inhibiting T cell activation and impairing T cell function.

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Scott, D., Gascoyne, R. The tumour microenvironment in B cell lymphomas. Nat Rev Cancer 14, 517–534 (2014). https://doi.org/10.1038/nrc3774

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